The neural circuitry of the dorsal horn of the spinal cord forms the basis for the mechanisms of pain and analgesia and the initial nervous system response to nerve injury. Our lab has made significant inroads in understanding the neuronal connectivity which subserves these phenomena through experiments involving multiple markers to identify interactions between neural elements. Fos protein coded by the c-fos proto-oncogene appear to be correlated with neuronal activity. In a rat model of peripheral inflammation and hyperalgesia, Fos protein has been shown to increase in the nuclei of a subpopulation of neurons concentrated in laminae I, II and V, areas of the spinal cord dorsal horn known to receive noxious inputs. Preproenkephalin mRNA (PPE) is induced in a subpopulation of spinal cord neurons in the same animal model. Using in situ hybridization histochemistry (ISHH) in combination with immunocytochemistry, PPE mRNA and Fos can be colocalized to a subpopulation of dorsal horn neurons. These data provide insights into the transcriptional events that occur in response to peripheral inflammation and hyperalgesia. Further characterization of changes in gene expression in spinal cord neurons in response to peripheral inflammation and hyperalgesia has identified an upregulation of preprotachykinin (PPT) mRNA. RNA blot analysis quantitated an 80% increase in PPT mRNA that was localized using ISHH to laminae I, II, and V/VI neurons. Combination of in situ hybridization with retrograde transport of fluoro-gold identified a subpopulation of these neurons as spinomesencephalic neurons. This observation suggests a role for tachykinin peptides in nociceptive CNS projection pathways. The dynamic response to nerve injury was examined following sciatic nerve transection using RNA blot and ISHH to localize changes in gene expression. These genes have been shown to be upregulated. The peptide products of these genes are neuropeptide Y, vasoactive intestinal polypeptide and galanin. The induction of these genes suggests an important role for these peptides in the response to injury.